This proposal seeks to develop a selective approach to metastatic gene discovery and is responsive to PA-03-100. The ability to directly select in vitro and in vivo for transcription factors that produce novel metastatic phenotypes in cancer cells is anticipated to have a significant impact on both our understanding of the cell biology of metastasis as well as the treatment of the disease. The study proposed here capitalizes on our development of designed transcription factors that enable activation or repression of endogenous genes. Polydactyl zinc finger proteins can now be prepared that recognize from 9 to 18 bp DMA target sequences with high affinity and specificity. When fused to activation or repression domains, these proteins become potent regulators of the transcriptional activity of the target genes. Currently no other gene therapy or gene tool strategy provides the means of both effectively knocking out and up-regulating the expression of an endogenous gene. This proposal focuses on the use of our transcriptional regulators to develop a new in vivo methodology for the exploration of genes involved in cell homing and metastasis in the context of the living animal. A genome-wide transcriptional modulation strategy will be developed and applied to the search for genes involved in metastasis and organ specific homing. The discovery of novel proteins key to metastasis could result in the development of a new class of cancer drugs and help to clarify the soil and seed metastasis hypothesis. With selective and potent transcriptional regulators we will address the potential of designed transcriptional regulators to prevent or otherwise alter the course of metastatic disease in animal models. The net result of this study should be an increased understanding of the cell biology of metastasis and the discovery of novel molecular targets for diagnostic, prognostic and therapeutic application.